No abstract

Behavioral measures are increasingly used to assess suicidal thoughts and behaviors. Some measures, such as the Suicide Stroop task, have yielded mixed findings in the literature. An understudied feature of these behavioral measures has been their psychometric properties, which may affect the probability of detecting significant effects and reproducibility. In the largest investigation of its kind, we tested the internal consistency and concurrent validity of the Suicide Stroop Task, drawing from seven separate studies (N=875 participants, 64% female, aged 12 to 81 years). Results indicated that the most common Suicide Stroop scoring approach, interference scores, yielded unacceptably low internal consistency (r=-.09-.13) and failed to demonstrate concurrent validity. Internal consistency coefficients for mean reaction times (RT) to each stimulus-type ranged from r=.93-.94. All scoring approaches for suicide-related interference demonstrated poor classification accuracy, AUCs=.52-.56 indicating that scores performed near chance in their ability to classify suicide attempters from non-attempters. In the case of mean RTs, we did not find evidence for concurrent validity despite our excellent reliability findings, highlighting that reliability does not guarantee a measure is clinically useful. These results are discussed in the context of the wider implications for testing and reporting psychometric properties of behavioral measures in mental health research.

HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy are primarily manifested as impaired behaviors, glial activation/neuroinflammation and compromised neuronal integrity, for which there are no effective treatments currently available. In the current study, we used doxycycline-inducible astrocyte-specific HIV Tat transgenic mice (iTat), a surrogate HAND model and determined effects of PNU-125096, a positive allosteric modulator of α7 nicotinic acetylcholine receptor (α7 nAChR) on Tat-induced behavioral impairments and neuropathologies. We showed that PNU-125096 treatment significantly improved locomotor, learning and memory deficits of iTat mice while inhibited glial activation and increased PSD-95 expression in the cortex and hippocampus of iTat mice. Using α7 nAChR knockout mice, we showed that α7 nAChR knockout eliminated the protective effects of PNU-125096 on iTat mice. In addition, we showed that inhibition of p38 phosphorylation by SB239063, a p38 MAPK-specific inhibitor exacerbated Tat neurotoxicity in iTat mice. Lastly, we used primary mouse cortical individual cultures and neuron-astrocytes co-cultures and in vivo staining of iTat mouse brain tissues and showed that glial activation was directly involved in the interplay among Tat neurotoxicity, α7 nAChR activation, and p38 MAPK signaling pathway. Taken together, these findings demonstrated for the first time that α7 nAChR activation led to protection against HAND and suggest that α7 nAChR modulator PNU-125096 hold significant promise for development of therapeutics for HAND.

HIV infection of astrocytes leads to restricted gene expression and replication but abundant expression of HIV early genes Tat, Nef and Rev. A great deal of neuroHIV research has so far been focused on Tat protein, its effects on astrocytes, and its roles in neuroHIV. In the current study, we aimed to determine effects of Nef expression on astrocytes and their function. Using transfection or infection of VSVG-pseudotyped HIV viruses, we showed that Nef expression down-modulated glial fibrillary acidic protein (GFAP) expression. We then showed that Nef expression also led to decreased GFAP mRNA expression. The transcriptional regulation was further confirmed using a GFAP promoter-driven reporter gene assay. We performed transcription factor profiling array to compare the expression of transcription factors between Nef-intact and Nef-deficient HIV-infected cells and identified eight transcription factors with expression changes of 1.5-fold or higher: three up-regulated by Nef (Stat1, Stat5, and TFIID), and five down-regulated by Nef (AR, GAS/ISRE, HIF, Sp1, and p53). We then demonstrated that removal of the Sp1 binding sites from the GFAP promoter resulted in a much lower level of the promoter activity and reversal of Nef effects on the GFAP promoter, confirming important roles of Sp1 in the GFAP promoter activity and for Nef-induced GFAP expression. Lastly, we showed that Nef expression led to increased glutamate uptake and decreased glutamate release by astrocytes and increased astrocyte proliferation. Taken together, these results indicate that Nef leads to down-modulation of GFAP expression and alteration of glutamate metabolism in astrocytes, and astrocyte proliferation and could be an important contributor to neuroHIV.

Ancient texts present the reader with an insurmountable challenge—namely, distance. Concerning the book of Lamentations, which was a response to the destruction of the Temple in 586 bce, readers are too removed from the raw experience of grief that gave rise to the lament in the first place. One way to overcome this obstacle—though imperfectly—is to juxtapose the book of Lamentations with a more recent and better documented horror. This article offers an analysis of women and children in Lamentations juxtaposed with the experiences of women and children in the Holocaust. The goal in this study is not to replace the experience of the destruction of the Temple with the Holocaust; rather, it is to reinvigorate the book of Lamentations, prompting the reader to move from apathy to empathy.